Lipids and lipid compositions for the delivery of active agents

Abstract

This invention provides for a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein R 1 -R 4 , L and X are defined herein. The compounds of formula (I) and pharmaceutically acceptable salts thereof are cationic lipids useful in the delivery of biologically active agents to cells and tissues.

1 . The present invention provides for a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         L is C 1-6  alkylene, C 2-6  alkenylene, C 2-6  alkynylene, —(CH 2 ) s —C 3-7 cycloalkylene-(CH 2 ) s —, —(CH 2 ) s —C 3-7  cycloalkenylene-(CH 2 ) s —, —(CH 2 ) s —C 3-7  cycloalkynylene-(CH 2 ) s —, *—C 1-4  alkylene-L2-, *—C 1-4  alkylene-L2-C 1-4  alkylene-, 
       
       
         
           
           
               
               
           
         
          wherein in the * denotes attachment of the moiety to the NR 1 R 2  group;
 L2, attached in either direction, is —O—, —S—, —C(O)—, —C(O)O—, —OC(O)O—, —CONH—, S(O) 2 NH—, NHCONH— or —NHCSNH—; 
 each s is independently 0, 1 or 2; 
 each t is independently 0, 1, 2, 3, or 4; 
 u is 0, 1, 2, 3, 4, 5, or 6; 
 
         R 1  and R 2  are each independently optionally substituted C 1-6  alkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted C 3-7  cycloalkyl-(CH 2 ) s —, optionally substituted C 3-7  cycloalkenyl-(CH 2 ) s —, optionally substituted C 3-7  cycloalkynyl-(CH 2 ) s —, or optionally substituted phenyl-(CH 2 ) s —; wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 3-7  cycloalkenyl, C 3-7  cycloalkynyl, and phenyl are optionally substituted with one or two substituents each independently selected from the group consisting of: OH, C 1-3  alkoxy, COOH, and COO—C 1-4  alkyl,
 or 
 
         R 1  and R 2  are joined together forming an optionally substituted 4-12 membered heterocyclic ring, said heterocyclic ring being optionally substituted with one to three substituents each independently selected from the group consisting of: OH, halo, C 1-3  alkyl, C 1-3  alkoxy, dimethylamino, —COO—C 1-4  alkyl, phenyl, piperidinyl, and morpholinyl; 
         R 3  and R 4  are each independently:
 (a) —Z 1 —R a , 
 (b) —Z 1 —R b —Z 2 —R a , 
 (c) —Z 1 —R b —Z 2 —R b —Z 3 —R a , 
 (d) —Z 1 —R b —Z 2 —R b —Z 3 —R b —Z 4 —R a , 
 (e) —R b —Z 1 —R a , 
 (f) —R b —Z 1 —R b —Z 2 —R a , 
 (g) —R b —Z 1 —R b —Z 2 —R b —Z 3 —R a , 
 (h) —R b —Z 1 —R b —Z 2 —R b —Z 3 —R b —Z 4 — R a , 
 (i) —R c , 
 (j) —Z 1 —R b —R c , or 
 (k) —R b —Z 1 —R b —R c ; 
 wherein Z 1 , Z 2 , Z 3 , and Z 4 , attached in either direction, are each independently —O—, —C(O)O—, —OC(O)O—, or —CONH—; 
 R a  is C 2-22  alkyl, C 2-22  alkenyl, or C 2-22  alkynyl; 
 each R b  is independently C 1-20  alkylene, C 2-20  alkenylene, or C 2-20  alkynylene; 
 R c  is 
 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
             R is C 5-22  alkyl, C 5-22  alkenyl, or C 5-22  alkynyl; 
             n is 0-12; 
             m, p, and q are each independently 0, 1, 2, 3 or 4; 
           
           provided that chains (a)-(h) have 12-30 carbon atoms and chains (i)-(k) have 12-70 carbon atoms; 
         
         X is CR 6  or N; and 
         R 6  is H, halo, C 1-6  alkyl, or R 4 ; or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound according to  claim 1  wherein X is CR 6 ; or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The compound according to  claim 2  wherein R 6 ; is H, chloro, bromo, or C 1-3  alkyl or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The compound according to  claim 3  wherein R 6  is H; or a pharmaceutically acceptable salt thereof. 
     
     
         5 . The compound according to  claim 4  wherein L is C 1-6  alkylene, *—C 1-4  alkylene-L2-, *—C 1-4  alkylene-L2-C 1-4  alkylene-, or 
       
         
           
           
               
               
           
         
          or a pharmaceutically acceptable salt thereof. 
       
     
     
         6 . The compound according to  claim 5  wherein R 1  and R 2  are each independently optionally substituted C 1-6  alkyl or R 1  and R 2  are joined together forming an optionally substituted 4-7 membered heterocyclic ring; or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The compound according to  claim 6  wherein:
 L is methylene, ethylene, or propylene, or 
 L is *—C 1-3  alkylene-OC(O)— or 
 L is *—C 1-4  alkylene-L2-C 1-2  alkylene-, wherein L2, attached in either direction, is C(O)O or OC(O)O; or a pharmaceutically acceptable salt thereof. 
 
     
     
         8 . The compound according  claim 7  wherein R 1  and R 2  are each independently optionally substituted methyl or optionally substituted ethyl; or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The compound according to  claim 4  wherein L-NR 1 R 2  group of formula (I) is selected from the group consisting of: 
       
         
           
                 
               
                     
                 
                   Structure 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         wherein each dashed line indicates the point of attachment to formula (I); or a pharmaceutically acceptable salt thereof. 
       
     
     
         10 . The compound according to  claim 9  wherein R 3  and R 4  are each independently:
 (a) —Z 1 —R a , 
 (b) —Z 1 —R b —Z 2 —R a , 
 (c) —Z 1 —R b —Z 2 —R b —Z 3 —R a , 
 (e) —R b —Z 1 —R a , 
 (f) —R b —Z 1 —R b —Z 2 —R a , 
 (g) —R b —Z 1 —R b —Z 2 —R b —Z 3 —R a , 
 (i) —R c , or 
 (j) —Z 1 —R b —R c ; or a pharmaceutically acceptable salt thereof. 
 
     
     
         11 . The compound according to  claim 10  wherein R 3  and R 4  are each independently:
 (a) —Z 1 —R a , 
 (b) —Z 1 —R b —Z 2 —R a , or 
 (f) —R b —Z 1 —R b —Z 2 —R a ; or a pharmaceutically acceptable salt thereof. 
 
     
     
         12 . The compound according to  claim 11  wherein R 3  and R 4  are each independently (b) —Z 1 —R b —Z 2 —R a ; or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The compound according to  claim 12  wherein Z 1  is —O—; R b  is C 1-10  alkylene; Z 2  is —OC(O)—; and R a  is C 5-18  alkyl or C 11-18  alkenyl having one to three double bonds; or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The compound according to  claim 10  wherein R 3  and R 4  are each independently (i) —R c ; R c  is c1 or c3; n is 1 or 2; m is 0 or 1; and p is 1; or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The compound according to  claim 1  wherein R 4  and R 3  are the same; or a pharmaceutically acceptable salt thereof. 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . A lipid composition comprising a compound according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The lipid composition according  claim 18  further comprising a mRNA. 
     
     
         20 . (canceled) 
     
     
         21 . The lipid composition according to  claim 19  further comprising a helper lipid, a neutral lipid, or a stealth lipid, or a combination thereof. 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . The lipid composition according to  claim 21  wherein the helper lipid is cholesterol, the neutral lipid is DSPC, and the stealth lipid is PEG-DMG, S010, or S011. 
     
     
         25 . The lipid composition according to  claim 24  in the form of a lipid nanoparticle. 
     
     
         26 - 29 . (canceled)